Retroviruses are responsible for many deadly diseases including cancer, leukaemia and AIDS. Retroviruses, unlike typical viruses, are RNA viruses. An enzyme in retroviruses transcribes their RNA into a DNA molecule that can integrate with a host's DNA. Once in a host cell, a retrovirus can take control of the cell's machinery and replicate itself.
Gammaretroviruses are considered zoonotic viruses because they are found in many different mammalian species, such as mice, cats, pigs, primates, cows, and birds.
Endogenous retroviruses result from infection and integration of retroviral proviruses into the germline, whereafter they are transmitted vertically as inherited genetic elements.
The first retroviruses discovered caused cell-free transmission of sarcomas and acute leukemias in chickens. Although these findings were initially met with skepticism, subsequent studies led to discovery of mouse mammary tumor virus and murine leukemia virus (MLV). Studies of animal retroviruses also revealed the existence of endogenous (germline-transmitted) retroviruses and of viral oncogenes and cellular proto-oncogenes.
The existence of oncogenic animal retroviruses raised the question of whether human oncogenic retroviruses also exist. After several false starts, clinical and epidemiological studies in Japan ultimately led to isolation of the first oncogenic human retrovirus, Human T-cell leukemia virus type I (the causative agent of adult T-cell leukemia) in 1980. Subsequently, the retrovirus HIV-1 was identified as the cause of acquired immunodeficiency syndrome and xenotropic murine leukemia virus-related virus (XMRV) was discovered.
All retroviruses carry three genes gag, pol and env that encode the viral core proteins, enzymes (reverse transcriptase, integrase and protease) and envelope proteins respectively. During infection virions bind to receptors on the cell surface and the viral cores are internalized and partially uncoated. In the infected cell, core-associated reverse transcriptase reverse-transcribes the viral RNA into double-stranded viral DNA that enters the nucleus where it is integrated (by way of integrase) into host DNA to generate the provirus. The provirus is then transcribed by cellular RNA polymerase II into full-length viral RNA. This RNA is transported to the cytoplasm (with and without splicing) to give viral mRNAs for synthesis of viral proteins; unspliced viral RNA is also transported to the cytoplasm as genomes for new virus particles. New virions bud from the cell surface without lysing the infected cell.
As a consequence of reverse transcription, the viral DNA is longer than the viral RNA by the presence of long terminal repeats (LTRs) at either end. In the integrated provirus, the LTRs contain the promoter and enhancer sequences necessary for initiation of viral transcription, as well as sequences for cleavage/polyadenylation. The LTR is subdivided into three regions: U3, R and U5; the promoter and enhancer sequences are contained in the U3 region.
The mechanism by which most retroviruses induce cancers is insertional activation of proto-oncogenes. Normally during infection retroviral DNAs are inserted at multiple, almost random sites in the cellular DNA. However, independent tumors induced by the same retrovirus often show integration at common insertion sites. These integration sites are largely at or near cellular proto-oncogenes—normal cell genes involved in positive stimulation of cell division and growth. The viral DNA leads to overexpression of the proto-oncogene RNA and protein, either by read-through transcription from the viral LTR (promoter insertion) or activation of the proto-oncogene’s own promoter by the retroviral enhancers. A subset of retroviruses that rapidly induce cancers carry viral oncogenes—genes that directly cause oncogenic transformation.8 The viral oncogenes result from capture of cellular proto-oncogenes into the viral genome.